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New therapeutic approaches for MND based on ER stress inhibition


Howard Florey Institute

Year Of Grant:



Motor Neuron Disease,


Bradley Turner


This proposal was based on our previous studies demonstrating that endoplasmic reticulum (ER) stress pathways are active in MND patients and transgenic rodent models. Here, we proposed to test the effects of three drug inhibitors of ER stress delivered systemically to MND mice.
Aim 1. Does ER stress inhibition slow disease progression, measured by motor function and survival, in MND mice?
Aim 2. Does ER stress inhibition protect against motor neuron death in MND mice?
Aim 3. Is there biochemical evidence of ER stress inhibition on the unfolded protein response in vivo?


Publications arising directly from this grant:
All papers acknowledged support from the BGRF.
1. Soo KY, Atkin JD, Horne MK, Nagley N (2009) Recruitment of mitochondria into apoptotic signaling correlates with the presence of inclusions formed by amyotrophic lateral sclerosis-associated SOD1 mutations. PMID 19046404. Citations = 2.
2. Walker AK, Farg MA, Bye CR, McLean CA, Horne MK, Atkin JD (2010) Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis. Brain 133:105-116. PMID 19903735.
3. Nagley P, Higgins GC, Atkin JD, Beart PM (2010) Multifaceted deaths orchestrated by mitochondria in neurons. Biochimica Biophysica Acta 1802:167-185. PMID 19751830
SBN 978-1-61470-101-9
Editors: B. Turner and J. Atkin, pp. © 2011 Nova Science Publishers, Inc
Chapter 2: Membrane Trafficking Defects as
Determinants of Motor Neuron
Susceptibility and Degeneration in ALS

Publications in preparation:
Another 3 publications currently in preparation will acknowledge the funding received by the BGRF; copies will be provided once the manuscripts are in press.

Conference abstracts arising from this grant:
All platform communications acknowledged support from the BGRF.
1. Walker A, Turner B, Farg M, McLean C, Horne MK, Atkin J. Protein disulphide isomerase is S-nitrosylated in ALS. 20th International Symposium on ALS/MND, Berlin, 8-10 December 2009.
2. Atkin J, Farg M, Walker A, Turner B, Horne M. Protein disulphide isomerase in CSF - a novel therapeutic and/or biomarker for ALS? 20th International Symposium on ALS/MND, Berlin, 8-10 December 2009.
3. Turner B, Farg M, Horne M, Atkin J. Dysfunction of the endosome pathway induced by SOD1 mutants. 20th International Symposium on ALS/MND, Berlin, 8-10 December 2009.


We recently identified a pathway in nerve cells called "ER stress" that is involved very early in MND. In this proposal jointly funded by the BGRF, MND Research Institute and NHMRC, we tested several drugs that block this pathway in MND mice. One compound slowed the appearance of symptoms in mice and importantly saved motor neurons from death. This gives support that ER stress may be a useful target for MND. This lead compound will be taken further to explore its therapeutic potential in MND.

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